Inhibition of lethal factor protease activity from anthrax toxin

Abstract

The present invention provides compounds that efficiently and specifically inhibit lethal factor (LF) protease activity of anthrax toxin.

1 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein
 each R 1  independently alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, COOR 7 , C(═O)R 7 , NR 7 R 8  or —X—Y—Z; 
 each Z is independently hydrogen, aryl, heteroaryl, heterocycle or cycloalkyl; optionally substituted with 1, 2 or 3 alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, COOR 7 , C(═O)R 7 , or NR 7 R 8 ;
 X is O, CO, NH, S or CH 2 ; 
 Y is O, CO, NH, S or CH 2 ; 
 L is O, S or NH; 
 K is N or CH; 
 each R 7  and R 8  are independently hydrogen, alkyl or aryl; and 
 n is 1, 2, 3, 4 or 5; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of  claim 1 . 
     
     
         3 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or phenyl, optionally substituted with 1, or 2 substituents independently selected from halo, —NO 2 , —COOH, or —SO 2 NH 2 ; 
         R 2  is, —CH 2 COOH, or a pharmaceutically acceptable salt thereof; 
         wherein, 
         X is O, NH, S, or CH 2 ; 
         Y is N or CH; and 
         Z is N or CH. 
       
     
     
         4 . The compound  claim 3  wherein R 1  is nitrophenyl, halophenyl, dihalophenyl, carboxy-phenyl, or halonitrophenyl. 
     
     
         5 . The compound  claim 3  wherein R 1  is dichlorophenyl, fluorophenyl, iodophenyl, carboxy-phenyl, chlorocarboxy-phenyl, or halonitrophenyl. 
     
     
         6 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and the compound of  claim 3 . 
     
     
         7 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of  claim 7 . 
     
     
         9 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen or phenyl, optionally substitutes with 1, or 2 substituents independently selected from halo, —NO 2 , or —SO 2 NH 2 ; 
         R 2  is, —(CH 2 ) 1-3 COOH, or a pharmaceutically acceptable salt thereof; 
         wherein 
         X is O, NH, S, or CH 2 ; 
         Y is N or CH; and 
         Z is N or CH. 
       
     
     
         10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and the compound of  claim 9 .